Inflammation, Sanitation, and Consternation: Loss of Contact With Coevolved, Tolerogenic Microorganisms and the Pathophysiology and Treatment of Major Depression
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CONTEXT: Inflammation is increasingly recognized as contributing to the pathogenesis of major depressive disorder (MDD), even in individuals who are otherwise medically healthy. Most studies in search of sources for this increased inflammation have focused on factors such as psychosocial stress and obesity that are known to activate inflammatory processes and increase the risk for depression. However, MDD may be so prevalent in the modern world not just because proinflammatory factors are widespread, but also because we have lost contact with previously available sources of anti-inflammatory, immunoregulatory signaling. OBJECTIVE: To examine evidence that disruptions in coevolved relationships with a variety of tolerogenic microorganisms that were previously ubiquitous in soil, food, and the gut, but that are largely missing from industrialized societies, may contribute to increasing rates of MDD in the modern world. DATA SOURCES: Relevant studies were identified using PubMed and Ovid MEDLINE. STUDY SELECTION: Included were laboratory animal and human studies relevant to immune functioning, the hygiene hypothesis, and major depressive disorder identified via PubMed and Ovid MEDLINE searches. DATA EXTRACTION: Studies were reviewed by all authors, and data considered to be potentially relevant to the contribution of hygiene-related immune variables to major depressive disorder were extracted. DATA SYNTHESIS: Significant data suggest that a variety of microorganisms (frequently referred to as the "old friends") were tasked by coevolutionary processes with training the human immune system to tolerate a wide array of non-threatening but potentially proinflammatory stimuli. Lacking such immune training, vulnerable individuals in the modern world are at significantly increased risk of mounting inappropriate inflammatory attacks on harmless environmental antigens (leading to asthma), benign food contents and commensals in the gut (leading to inflammatory bowel disease), or self-antigens (leading to any of a host of autoimmune diseases). Loss of exposure to the old friends may promote MDD by increasing background levels of depressogenic cytokines and may predispose vulnerable individuals in industrialized societies to mount inappropriately aggressive inflammatory responses to psychosocial stressors, again leading to increased rates of depression. CONCLUSION: Measured exposure to the old friends or their antigens may offer promise for the prevention and treatment of MDD in modern industrialized societies.
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These immunoregulatory organisms reduce inflammation and suppress effector immune cells through induction of IL-10 and TGFβ while promoting anti-inflammatory immune cell populations such as M2 macrophages, regulatory T cells and regulatory B cells.
“these organisms (often referred to as ‘old friends’) share a tendency to reduce inflammation and suppress effector immune cells through the induction of IL-10 and transforming growth factor-β (TGFβ) while promoting the development of anti-inflammatory immune cell populations, such as alternatively activated (also referred to as ‘M2’) macrophages and regulatory T (TReg) cells and regulatory B cells”
From The role of inflammation in depression: from evolutionary imperative to modern treatment target (2016) · cites this paper as [13]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredModern humans are in a condition of exacerbated inflammatory bias, with particular conditions afflicting an individual largely resulting from genetic predisposition and environmental exposures, ultimately accounting for high comorbidity between depression and autoimmune, allergic and inflammatory disorders.
“Consequently, we find ourselves in a condition of an exacerbated inflammatory bias, with the particular conditions afflicting any given individual largely the result of genetic predisposition and environmental (for example, psychosocial) exposures13,14, ultimately accounting for the high co-morbidity between depression and autoimmune, allergic and inflammatory disorders13,15.”
From The role of inflammation in depression: from evolutionary imperative to modern treatment target (2016) · cites this paper as [13]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredEnvironmental risk factors for the development of depression - psychosocial stress, early life adversity, obesity and processed-food diet - are uniformly pro-inflammatory.
“Environmental risk factors for the development of depression (that is, psychosocial stress, early life adversity, obesity and processed-food diet) are uniformly pro-inflammatory13.”
From The role of inflammation in depression: from evolutionary imperative to modern treatment target (2016) · cites this paper as [13]
The section on environmental risk describes inflammation as a shared response to a diverse range of factors linked to depression. The section on psychosocial stress supports stress and early-life stress, and the Abstract’s Context identifies obesity as activating inflammatory processes. Our copy does not establish that a processed-food diet is pro-inflammatory or that the listed factors are uniformly so. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe prevalence of autoimmune, allergic and inflammatory diseases has markedly increased in the past 100 years, and rates follow a similar upward trajectory in societies transitioning from traditional rural to modern urban ways of life.
“The prevalence of autoimmune, allergic and inflammatory diseases has markedly increased in the past 100 years, and rates of these conditions follow a similar upward trajectory in societies transitioning from traditional (that is, rural) to modern (that is, urban) ways of life13.”
From The role of inflammation in depression: from evolutionary imperative to modern treatment target (2016) · cites this paper as [13]
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- Authors
- Raison, C. L., Lowry, C. A., & Rook, G. A. W.
- Affiliations
- Emory University (US)
- Venue
- Archives of General Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2010-12-06
- Volume
- 67
- Issue
- 12
- Pages
- 1211
- ISSN
- 0003-990X (ISSN-L)
- PMC
- PMC3724429
- OpenAlex
- W2077672919
- Cited by
- 169
- References
- 259
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 8 · 2023: 4 · 2022: 8 · 2021: 13 · 2020: 13 · 2019: 6 · 2018: 9 · 2017: 7 · 2016: 18 · 2015: 13 · 2014: 15 · 2013: 20 · 2012: 20
- FWCI
- 1.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Archives of General Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Science Foundation (0845550, 0921969)
- Bill and Melinda Gates Foundation
- Eli Lilly and Company
- European Commission
- Silence Therapeutics
- National Institutes of Health (UL1TR000454, RR025008)
- Centers for Disease Control and Prevention
- National Institute of Mental Health (R21 MH0771172, R01MH070553, R01MH086539, R01MH065702)
- National Center for Research Resources (UL1RR025008, M01RR000039, M01-RR-0039)
- National Center for Advancing Translational Sciences
- National Center for Complementary and Integrative Health (R01AT004698, RC1AT005728)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Keywords
- major depressive disorder, inflammation, hygiene hypothesis, old friends, microbial exposure, psychosocial stress, cytokines, autoimmune disease, inflammatory bowel disease, asthma, industrial society
- MeSH terms
- Animals, Anti-Inflammatory Agents, Major Depressive Disorder, Environmental Microbiology, Humans, Inflammation, Organic Chemicals, Sanitation, Social Environment, Stress, Psychological, Cytokines
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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